tbuckley/cabot-search huggingface dataset:
MODL-28. Patient-derived, three-dimensional organoid platform for pediatric brain tumor modeling
Authors: Valerie Baubet, David Beale, Santi Mariarita, Angela Viaene, Peter Madsen, Fadi Jacob, Guo-li Ming, Song Hongjun, Storm Phillip, Mateusz Koptyra, Resnick Adam
Journal: Neuro-Oncology (2022)

Abstract Brain tumors have become the leading cause of cancer-related death in children. An important hurdle to scientific and clinical progress in the field has been the limited availability of preclinical tumor models. Historically, few pediatric brain tumor cell lines have been established and these often poorly recapitulate the phenotypes of the original tumors. In recent years, the Children’s Brain Tumor Network (CBTN) has accelerated the development of patient-derived cell lines and xenografts, offering these resources to the community through open-source access. While these models are extremely valuable, their development process can be lengthy and result in clonally selected lines which presents a challenge for studying complex tumor biology. To address the need for three-dimensional tissue culture, our group in conjunction with CBTN, utilized organoid culture from fresh tissue specimens obtained directly from surgical resection of various pediatric brain tumor histologies. This resulted in the development and banking of over 30 organoid models, which included ependymoma, high-grade glioma, medulloblastoma, atypical teratoid-rhabdoid tumor, diffuse midline glioma, and low-grade glioma diagnoses. Tissue was processed within an hour post extraction and cultured with universal media composition for each diagnosis. Organoid growth was observed within 2-3 weeks of initiation and continued for up to three months before banking. Banked organoids established growth upon return to culture. Phenotypic analysis revealed organoid cell composition that represented clinical histology. Importantly, organoids returned to culture post-banking demonstrated similar cell composition to those in the original culture, indicating their utility for subsequent preclinical testing. Here we provide a simple and efficient workflow for the generation and characterization of three-dimensional tumor organoids generated from fresh surgical pediatric brain tumor tissue. The platform has the potential to accelerate investigations into tumor biology and empower a diverse array of translational studies for the pediatric brain tumor field.
Molecular aberrations in late-stage dedifferentiated/undifferentiated endometrial carcinoma: A review of current literature.
Authors: Ian Landry, Vikram Sumbly, Mallorie Vest, Mary K Smith Reed
Journal: Journal of Clinical Oncology (2022)

e17632 Background: Uterine cancer remains the fourth most common cancer diagnosed and seventh most common cause of cancer death in American women. Four molecular subtypes have been created to categorize and prognosticate endometrial carcinoma based on their molecular aberrations, but are often based on initial tumor presentation and are associated with high cost to the healthcare system. Methods: A comprehensive literature search was performed on PubMed, ClinicalTrials.gov, Embase, and WebofScience. Abstracts and publications from ASCO/ASH were also included. Results: 32 articles were included in our systematic review. A total of 388 women were analyzed in the main group analysis and nearly half of the patients were diagnosed as stage III or IV (n = 178, 46%). MSI was present in 66% of all tumors tested and PD-L1 was overexpressed in 78%. Eighty-four percent (84%) of the tumors were negative for ER, up to 44% had loss in SWI/SNF complex, and 64% lost expression of e-cadherin. Pax-8 and fascin proteins were over expressed in 29% and 88% of patients tested, respectively. In a sub-group analysis, evidence of progression and use of adjuvant radiotherapy were significantly associated with a later stage of diagnosis ( p = 0.052, 0.044). Conclusions: We found no statistically significant association between stage of diagnosis and unique mutation. Patients with evidence of progression or recurrence were found to have disease in atypical locations. Unique mutations which categorize patients at time of diagnosis may be different upon progression or recurrence of the tumor. While a novel classification system has been produced to assist with prognosis and treatment guidelines, these tests are not widely available in the community hospital setting.[Table: see text]
LGG-48. The influence of different FGFR1 alterations on pediatric low-grade glioma tumor biology and targeted therapy response
Authors: Eric Morin, Jeromy DiGiacomo, Dana Novikov, Seth Malinowski, Kin-Hoe Chow, David Jones, Sanda Alexandrescu, Keith Ligon, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract Pediatric low-grade gliomas (pLGGs) have excellent survival, however, with current standard of care, most patients suffer lifelong severe sequalae. pLGGs are almost exclusively driven by single activating mutations in the MAPK pathway. Clinical trials with small molecule inhibitors in BRAF-altered pLGGs are showing promising results in early clinical trials, and similar efforts are now underway for FGFR1-altered tumors, however the underlying biology and treatment response has not been thoroughly explored in a pre-clinical setting. To explore the genetic landscape of FGFR altered gliomas we assembled a cohort of 87 patients with FGFR1-4 altered gliomas across Dana-Farber Cancer Institute, Boston Children’s Hospital and Brigham and Women’s Hospital. Within this cohort we observed that pLGGs harboring FGFR1 kinase hotspot mutations (FGFR1-N546K or -K656E) frequently harbored a second alteration associated with activation of the MAPK or mTOR pathways, most commonly in the phosphatase PTPN11, NF1 or within the FGFR1 gene itself. Additionally, we observed two previously described structural variants of FGFR1, an FGFR1 internal kinase tandem duplication (FGFR-ITD) and a fusion with TACC1 (FGFR1:TACC1). The relative impact of the different FGFR1 alterations on oncogenicity, therapeutic response and resistance has not been previously explored. To address this, we have established mouse neural stem cell models overexpressing the structural variants and hot spot mutant FGFR1 alone or in combination with a second alteration. Immunoblotting revealed that the addition of a second alteration attenuated phosphorylation of ERK, AKT and S6 and influenced cell proliferation both in normal growth conditions and in absence of growth factor. Treatment with inhibitors of FGFR (Infigratinib) and MEK (Trametinib) revealed variable sensitivity both targeted therapies, suggesting that treatment of FGFR1 driven pLGG might require tailoring to the specific FGFR1 alteration.
Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes
Authors: Leah Guthrie, Sean Paul Spencer, Dalia Perelman, Will Van Treuren, Shuo Han, Feiqiao Brian Yu, Erica D. Sonnenburg, Michael A. Fischbach, Timothy W. Meyer, Justin L. Sonnenburg
Journal: Cell Host & Microbe (2022)
Trends in treatments and in-hospital outcomes of primary malignant cardiac tumors: A 16-year U.S. nationwide study.
Authors: Yesh Datar, Kanhua Yin, Michael J. Reardon, Nikola Dobrilovic
Journal: Journal of Clinical Oncology (2022)

e18756 Background: Primary malignant cardiac tumors are a rare but highly aggressive disease. Recent studies have quantified its long-term survival and the efficiencies of different treatment modalities. However, the trends in treatment patterns and in-hospital outcomes in the United States are still poorly understood. Methods: The National Inpatient Sample (NIS) was queried to identify adult patients (age ≥ 18) who were diagnosed with primary malignant cardiac tumors (ICD-9: 164.1; ICD-10: C38.0). Surgical treatments and chemotherapy were identified using the corresponding procedure and ICD codes. The national estimates were generated based on the weighted values of the hospitalizations. Results: From 2002 to 2017, 6,494 malignant cardiac tumor-related hospitalizations were identified. The mean age was 53.8 ± 17.5 years, 55.9% White, and 47.9% women. There was an increasing trend in the incidence over the study period, from 1.15 per 100,000 NIS admissions in 2002 to 1.49 per 100, 000 NIS admissions in 2017 (P for trend &lt; 0.001). 1708 (26.3%) patients received some forms of surgery: 733 (11.2%) underwent surgical excision of the tumor, 585 (9.0%) received pericardiotomy, and 397 (6.1%) underwent pericardiectomy. A decreasing trend in surgical therapy was observed (22.0% in 2002 to 16.8% in 2017, P for trend &lt; 0.001). 1403 (21.6%) patients received chemotherapy, with a significant decreasing trend over time (25.8% in 2002 to 19.6% in 2017, P for trend &lt; 0.001). The in-hospital mortality of the entire cohort was 11.1%, which remained unchanged over time (P for trend &gt; 0.05). Conclusions: This study demonstrates that although malignant cardiac tumor-related hospitalizations were increasing between 2002 and 2017, the uses of surgical therapy and chemotherapy were decreasing. The in-hospital mortality was high but remained stable over the study period.
OTHR-33. INTRODUCTION OF A MULTIDICIPLINARY NEURO ONCOLOGY LONG TERM FOLLOW UP CLINIC
Authors: Christine Dahl, Nicola Farrell, Nicola Blount, ryan Mould, Angela Simcox, Charlotte Malcolm, Anita Freeman, Vicky King, Daniel Bell, Antony Michalski, Hoong-Wei Gan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: The number of children and young people (CYP) surviving brain tumours is increasing annually with a doubling of 5-year survival over the last 40 years. More than two-thirds of these survivors suffer multiple long-term co-morbidities (“late effects”) from their tumour and/ or treatment(s) necessitating lifelong multiprofessional follow-up. This results in multiple appointments and increases the burden of care on patients. Method/Project description To establish a collaborative multidisciplinary “one stop shop” long-term follow-up clinic for CYP &amp;gt;5 years from the end of neuro-oncological treatment to the reduce the need for multiple hospital appointments and to provide holistic assessment and care.The first clinic began in January 2020 as a collaboration between the departments of neuro-oncology, endocrinology, neuropsychology, psychology, physiotherapy and occupational therapy. RESULTS: We have audited the last 60 patients seen in clinic in 2 years and the services they required both in and out of clinic are noted below: Endocrinology – 58 patients Educational help and formal neuropsychology (44 and 39 respectively) There are significant emotional problems in the group and 32 saw clinical psychology and 13 were referred to CAMHS. Physical function issues – 31 saw both physiotherapy and occupational therapy. 10 required referral to orthopaedics Neurology and neurosurgery (13 and 11 respectively) Visual impairment – 33 saw ophthalmology Hearing problems – 17 saw audiology Other organ dysfunction – 4 saw cardiology and 3 urology. We have some feedback data on patient and parent satisfaction with the clinic which shows 92% (13 of 14) families preferred to be seen in the MDT setting rather than by separate clinicians. DISCUSSION: Few models of similar multidisciplinary neuro-oncology long-term follow-up clinics exist in the UK with a lack of streamlined funding, despite recognition from families and professionals about their utility.
Not all adverse pathology features are equal: Identifying optimal candidates for adjuvant radiotherapy among patients with adverse pathology at radical prostatectomy
Authors: E. Mazzone, G. Gandaglia, A. Stabile, N. Fossati, A. Gallina, E. Zaffuto, M. Picozzi, F. Barletta, S. Scuderi, R. Leni, L. Nocera, G. Sorce, F. Pellegrino, G. Rosiello, U. Capitanio, A. Larcher, R. Lucianò, R. Montironi, A. Cimadamore, P.I. Karakiewicz, S. Shariat, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Improving preeclampsia risk prediction by modeling pregnancy trajectories from routinely collected electronic medical record data
Authors: Shilong Li, Zichen Wang, Luciana A. Vieira, Amanda B. Zheutlin, Boshu Ru, Emilio Schadt, Pei Wang, Alan B. Copperman, Joanne L. Stone, Susan J. Gross, Yu-Han Kao, Yan Kwan Lau, Siobhan M. Dolan, Eric E. Schadt, Li Li
Journal: npj Digital Medicine (2022)

Abstract Preeclampsia is a heterogeneous and complex disease associated with rising morbidity and mortality in pregnant women and newborns in the US. Early recognition of patients at risk is a pressing clinical need to reduce the risk of adverse outcomes. We assessed whether information routinely collected in electronic medical records (EMR) could enhance the prediction of preeclampsia risk beyond what is achieved in standard of care assessments. We developed a digital phenotyping algorithm to curate 108,557 pregnancies from EMRs across the Mount Sinai Health System, accurately reconstructing pregnancy journeys and normalizing these journeys across different hospital EMR systems. We then applied machine learning approaches to a training dataset ( N = 60,879) to construct predictive models of preeclampsia across three major pregnancy time periods (ante-, intra-, and postpartum). The resulting models predicted preeclampsia with high accuracy across the different pregnancy periods, with areas under the receiver operating characteristic curves (AUC) of 0.92, 0.82, and 0.89 at 37 gestational weeks, intrapartum and postpartum, respectively. We observed comparable performance in two independent patient cohorts. While our machine learning approach identified known risk factors of preeclampsia (such as blood pressure, weight, and maternal age), it also identified other potential risk factors, such as complete blood count related characteristics for the antepartum period. Our model not only has utility for earlier identification of patients at risk for preeclampsia, but given the prediction accuracy exceeds what is currently achieved in clinical practice, our model provides a path for promoting personalized precision therapeutic strategies for patients at risk.
Afatinib (Afa) + bevacizumab (Bev) versus afatinib alone as first-line treatment of patients with EGFR-mutated advanced non-squamous NSCLC: Primary analysis of the multicenter, randomized, phase II study—AfaBev-CS study.
Authors: Nobuhisa Ishikawa, Takashi Ninomiya, Toshiyuki Kozuki, Shoichi Kuyama, Koji Inoue, Toshihide Yokoyama, Nobuhiro Kanaji, Masayuki Yasugi, Takuo Shibayama, Keisuke Aoe, Nobuaki Ochi, Kazunori Fujitaka, Masahiro Kodani, Yutaka Ueda, Kazuhiko Watanabe, Akihiro Bessho, Keisuke Sugimoto, Isao Oze, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2022)

9112 Background: Adding Bev to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding Bev to a second-generation EGFR-tyrosine kinase inhibitor. AfaBev-CS is a Japanese no-profit, randomized, open-label, multicenter phase II trial of Afa plus Bev vs Afa alone as first-line treatment for EGFR-mutated advanced NSCLC. Methods: This study enrolled untreated pts of advanced non-squamous NSCLC harboring EGFR sensitizing mutation (Del19 or L858R) and without symptomatic brain metastases. 100 eligible pts were randomized in a 1:1 ratio to receive either Afa (30 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (AfaBev arm) or Afa (40 mg, daily) monotherapy (Afa arm), and stratified according to stage, EGFR mutation status and institution. The primary endpoint was PFS and the secondary endpoints were OS, tumor response and time to treatment failure. The sample size was set in terms of feasibility. The power is greater than 50% under the assumptions of a median PFS of 12 months for the Afa arm and HR of 0.6 for the AfaBev arm, with an accrual of 2.5 years and a minimum planned follow-up period of 2 years with the type 1 error of 0.05 (two-sided). Results: Between August 2017 and September 2019, 100 pts were enrolled (each arm, 50 pts). At a median follow-up of 31.3 months for all randomized pts, total 69 events occurred. Median PFS was 16.3 months for AfaBev arm and 16.1 months for Afa arm, with a hazard ratio (HR) of 0.865 (95%CI, 0.539 – 1.388; loglank p = 0.5476). In subgroup analysis, pts &lt; 70 years old (HR 0.347) and pts with brain metastasis (HR 0.353) showed better trend of PFS in AfaBev arm. On the other hand, pts ≥ 70 years old (HR 1.738) and pts without brain metastasis (HR 1.196) did not show better trend in AfaBev arm. In terms of OS, result was immature because number of events was still small. Objective response rate was 77.6% in AfaBev arm and 72.0% in Afa arm. Severe adverse events were observed in 11 pts for each arm. Grade 3 or more diarrhea, hypertension, rash acneiform, paronychia and stomatitis were frequently observed in AfaBev arm. Pneumonitis was not observed for AfaBev arm and observed in 3 (6.0%) for Afa arm, and grade 3 in one patient. Conclusions: This study failed to show the efficacy of AfaBev arm for improving PFS in untreated pts with EGFR mutated non-squamous NSCLC. In pts &lt; 70 years old, Afa plus Bev might be promising. Clinical trial information: jRCTs061180006.
Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.
Authors: Snehal Patel, David McWilliams, Jaye Thompson, Mira Patel, F. Joseph Daugherty
Journal: Journal of Clinical Oncology (2022)

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.
<sup>64</sup>Cu-SAR-Bombesin PET-CT imaging in the staging of ER+/PR+/HER2- metastatic breast cancer: Safety, dosimetry, and feasibility in a phase I trial.
Authors: Keith Wong, Gemma Sheehan-Dare, Andrew Nguyen, Bao Ho, Victor Liu, Jonathan Lee, Lauren Julia Brown, Rachel Fitz-Gerald Dear, Lyn Chan, Sarennya Pathmanandavel, Shikha Sharma, Alessandra Malaroda, Isabelle Smith, Elgene Lim, Louise Emmett
Journal: Journal of Clinical Oncology (2022)

3092 Background: Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and 18 F-Fluorodeoxyglucose PET-CT (FDG) used in conventional staging of breast cancer has lower sensitivity for these subtypes. Gastrin releasing peptide receptors (GRPR) are a potential alternative diagnostic and theranostic target for ER+/PR+ breast cancers due to their overexpression of GRPR. This phase 1 study aims to assess the safety and potential of the novel radiotracer 64 Cu-Sarcophagine(SAR)-Bombesin (BBN) in the re-staging of recurrent metastatic ER+/PR+/human epidermal growth factor 2 negative (HER2-) breast cancer. Methods: Patients with confirmed recurrent or primary metastatic ER+/PR+/HER2- breast cancer undergoing staging prior to a new treatment underwent 64 Cu-SAR-BBN PET-CT with imaging at 1, 3 and 24 hours post-injection. Bloods and vital signs were acquired for patients at baseline, 1, 3 and 24 hours post-injection timepoints, and electrocardiogram (ECG) performed 1 hour pre and 1 hour post injection. Blood tracer-clearance and dosimetry was performed. GRPR receptor status was assessed in 4/7 patients from metastatic-site biopsy samples. Staging of the patients was assessed by conventional imaging (FDG, bone scan and diagnostic CT) within 3 weeks of 64 Cu-SAR-BBN imaging. All PET scans were assessed visually, and quantitatively using MIM Software. Results: 9 patients were enrolled. 7/9 patients underwent all imaging modalities, while 2/9 did not undergo BBN imaging. 1/7 patient who underwent all imaging had de- novo metastatic ER+/PR+/Her 2- breast cancer and 6/7 recurrent metastatic disease. 2/7 had lobular subtype. There were no adverse events reported, and ECG, vitals and haematological, biochemical and coagulation markers remained unchanged. All 7 patients were positive on conventional imaging, while 6/7 were positive on FDG. BBN was positive in 5/7 patients. Both BBN negative patients had disease identified on FDG. Conversely, 1 patient was BBN positive but FDG negative. 4/7 patients were BBN positive and FDG positive. In these 4 patients, mean SUVmax was higher for BBN than FDG (15 vs. 12). In classical lobular subtype (2/7), BBN was highly avid compared to FDG (SUV max 20 vs 11, and 20 vs &lt;3) and with a higher tumor volume compared to FDG (2034 vs 504, and 634 mL vs FDG negative). Conclusions: 64 Cu-SAR-Bombesin is a novel tracer which appears safe and may have a diagnostic and theranostic role in patients with metastatic ER+/PR+/HER2- breast cancer, particularly lobular subtype. Further evaluation appears warranted.